Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full.
Noroviruses (NVs) are Category B biodefense agents and widely accepted as the major cause of viral gastroenteritis (GE). Less than 20 particles can establish a NV infection and prior exposure does not lead to protection from a repeat infection. The CDC has estimated that 64,000 hospitalizations and 900,000 clinical visits among children result from NV infection in developed countries alone (1, 2). In developing countries, NVs account for up to 200,000 deaths annually in children <5 years of age (1). Asymptomatic shedding of NVs is also a significant uncharacterized problem, with up to 12% of the UK population actively secreting virus during a study period from 1993 to 1996. At least 50% of children under age 5 are seropositive for NV exposure; this increases to 60-90% by age 10 and reaches 100% by adulthood (3). NVs are a significant cause of morbidity and mortality in immune-compromised patients, particularly those undergoing chemotherapy or stem cell transplants (4-12).
The idea that NVs cause an acute self-limiting disease with no long-lasting sequelae is under challenge. NV infections in infants can lead to seizures (13, 14) and have been linked to necrotizing enterocolitis (15). In adults NV infection can exacerbate inflammatory bowel disease (16). Increased disease severity has been linked to the use of Statins to regulate cholesterol levels in the elderly (17). Cultured cells treated with Statins show increased NV replication (18). This is especially a concern, given that 24 million Americans used Statins in 2004 and use is increasing (19).
Despite their impact on human health, NVs are one of the most poorly characterized viral groups. Studies of human NVs and the development of therapeutics are hampered by their inability to infect cells. Vaccine development is being actively pursued. However, challenges here include NVs using multiple mechanisms to persist in human populations, complex antigenic diversity and rapid virus evolution (3). Moreover, even if a vaccine should become available certain patients having genetic immune deficiencies would be unable to take such a vaccine. Clearly, a need exists in the art for improved antiviral agents which effectively and specifically inhibit norovirus replication.